IRFP: Total Synthesis and Biological Evaluation of Dictyoxetane

Ciesielski Jennifer, Rochester, Ny NY

Investigators

Abstract

The International Research Fellowship Program enables U.S. scientists and engineers to conduct nine to twenty-four months of research abroad. The program's awards provide opportunities for joint research, and the use of unique or complementary facilities, expertise and experimental conditions abroad. This award will support a twenty-four-month research fellowship by Dr. Jennifer Ciesielski to work with Prof. Dr. Erick M. Carreira at the Swiss Federal Institute of Technology (ETH), in Zurich, Switzerland. Until recently, oxetanes have been an underrepresented class of compounds. The laborious synthetic effort required to assemble these four-membered rings has prevented their use in organic synthesis. However, contemporary applications of oxetanes in synthetic, medicinal, polymer, and agrochemistry have fueled an influx of intriguing methodologies for their design. Although only a few natural products contain the oxetane motif, most of them, for example taxol®, docetaxel, and thromboxane A2, are extremely biologically active and represent pharmaceutical hits. Studies have already demonstrated that the presence of this motif was critical to the potency of these natural products, but the exact role of oxetane moiety has not been clearly defined. Amongst the oxetane containing natural products, dictyoxetane presents a unique synthetic challenge and the opportunity to gain a better understanding of its biological relevance, especially the role of the oxetane. To date, no total synthesis has been reported and the absolute configuration has not been established. Additionally, biological assays have shown that the core of this molecule, the portion that contains the oxetane, has a great potential towards human gastronomic carcinoma. Therefore, a synthetic route to this molecule could provide a foray into its potentially important pharmacological activity. The goal of this research will be to develop an efficient route to dictyoxetane, examine its biological activity, and, finally, investigate the role of the oxetane moiety by synthesizing non-natural derivatives. During this endeavor, novel synthetic methods will also be developed, which will be both general and tailored to this natural product. Exploring uncharted territories is the foundation of chemistry, and science in general. It is these explorations that open the doors for new and interesting discoveries beyond the intended research objective. The proposed project on dictyoxetane is a perfect example of this kind of venture. Although recent endeavors have unveiled the potential of oxetanes in drug discovery, its implications in the context of natural products are far from clear. The development of this project could result in major advances in the exciting field of oxetane chemistry. This work is not limited to the synthesis of dictyoxetane and its bioactive evaluation, it will also allow us to gain a better understanding of the oxetane functionality for the future design of new biologically active products. Depending on our results, applications can be envisioned for both academic and industrial research.